Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
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DOI：
10.1038/s41467-020-15694-y
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发表时间：
2020-05-14
影响因子：
16.6
通讯作者：
Hetz, Claudio
中科院分区：
文献类型：
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作者：
Dufey, Estefanie;Bravo-San Pedro, Jose Manuel;Hetz, Claudio
维持基因组完整性和蛋白质平衡的动态平衡系统之间的分子联系还知之甚少。在这里，我们确定了在基因毒性应激下，未折叠蛋白反应转导通路IRE1α的选择性激活，以调节修复程序和维持细胞生存。在缺乏内质网(ER)应激信号的情况下，DNA损伤参与了IRE1α信号的传递，导致受调控的IRE1α依赖衰变(RIDD)的独占激活，而不激活其由转录因子XBP1介导的规范输出。IRE1α内切核酸酶活性控制参与DNA损伤反应、影响DNA修复、细胞周期停滞和细胞凋亡的mRNAs的稳定性。C-Abl激酶被DNA损伤激活，触发IRE1α的寡聚反应，催化RIDD。在果蝇和小鼠中，IRE1α在遗传毒性应激下的保护作用是保守的。总之，我们的结果揭示了维持基因组稳定和蛋白质稳定的分子途径之间的重要交集。IRE1α通过促进XBP1的非常规剪接和RNA的选择性切割，在未折叠蛋白反应(UPR)中发挥关键作用。在这里，作者报告说，IRE1α在DNA损伤反应时被激活，并选择性地控制mRNAs的稳定性，以维持基因组的完整性。
The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1 alpha under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1 alpha signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1 alpha -dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1 alpha endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1 alpha to catalyze RIDD. The protective role of IRE1 alpha under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis. IRE1 alpha plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1 alpha is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.